PA/PH/CEP (16) 58 2015-2016年度化学纯度CEP新申报资料十大缺陷

翻译 ：Julia  来源：Julia法规翻译

PA/PH/CEP (16) 58

Strasbourg, December 2016 

Certification of suitability to the Monographs of the EuropeanPharmacopoeia 

TOP TEN DEFICIENCIES

New Applications for Certificates of Suitability forchemical purity

(2015-2016) 

2015-2016年度化学纯度CEP新申报资料十大缺陷 

Address: 7 AlléeKastner, CS 30026 F-67081 Strasbourg (France)

Tel: +33 (0) 3 88 4130 30 – Fax: +33 (0) 3 88 41 27 71 - e-mail: [email protected]

Internet: http://www.edqm.eu

Thisdocument is a summary of the ten most frequent questions raised after theinitial evaluation of new applications for Certificates of suitability (CEP)for chemical purity. It is based on the content of a sample of 20 deficiencyletters sent selected randomly during the second half of 2015 and beginning of2016.

本文是对化学纯度CEP新申报资料初次审评中发现的最常见十大问题的总结。该总结是基于2015年下半年和2016年初期间随机抽取的20封缺陷信内容。

The topten most frequent questions are listed below together with expectations andrecommendations on how to address the specific deficiencies, with reference toapplicable guidelines.

以下列出了十大最常见问题，以及EDQM期望和建议如何解决这些缺陷和相关的适用指南。

Thisdocument is intended to help applicants to improve the quality of theirdossiers, in order to facilitate and speed up the granting of their CEPs. Itshould be taken into account while building up a dossier, in combination withthe EDQM Guideline “Content of the Dossier for Chemical Purity andMicrobiological Quality (PA/PH/CEP 04 1)” available on the EDQM website.

本文意在帮助申报人提高其注册文件质量，以帮助和加快其CEP的颁发。在构建注册文件时，应结合考虑EDQM官网上EDQM指南“化学纯度和微生物质量注册文件内容（PA/PH/CEP04 1）”的要求。

This isapplicable to sources of substances which have not yet been introduced inmedicinal products available on the European market.

此点适用于目前尚未用于欧洲市场上销售的药品生产的物质来源。

Applicantsare expected to provide a complete discussion on mutagenic impurities in theirapplication for a CEP. It is necessary to refer to ICH M7 (in force sinceJanuary 2016). Any addendum, available on the ICH website, may also be usefulreading for product-specific recommended safety values (refer also to Note 5 ofICH M7).

申报人应在其CEP注册申报资料中提交关于诱变性杂质的完整讨论。该讨论应参考ICH M7（自2016年1月起生效）。ICH官网上所有备忘也可能会对于特定产品所推荐的安全值有用（同时也请参考ICH M7注5）。

It isexpected that potential mutagenic impurities arising from the synthesis of thesubstance and its starting materials (if relevant and if not otherwisejustified) or from degradation processes are listed and classified in the CEPdossier as per ICH M7. Impurities can be classified with respect to theirmutagenic and carcinogenic potential in 5 different classes (refer to table 1of ICH M7) and actions for control are proposed accordingly. Sometimes nomutagenicity data are available for impurities showing alerting structures andarising from synthetic processes (class 3 impurities as per ICH M7); theseimpurities should be controlled at or below an acceptable limit or mutagenicityassays should be conducted (refer to Note 2 of ICH M7) in order to understandif the impurity is non-mutagenic (hence class 5) or mutagenic (hence class 2).The outcome of bacterial mutagenicity assays can also be predicted by (Q)SARmethodologies (in-silico studies). According to ICH M7 two (Q)SAR methodologiesthat complement each other should be applied, one which is expert rule-basedand a second one which is statistical-based. The principles set by the OECDshould be followed.

应按ICH M7的分类在CEP注册文件中分类列出原料药合成过程中、起始物料合成过程中（如相关并且没有另做论证时）以及原料药降解过程中所产生的潜在诱变性杂质。杂质可以按其诱变性和致癌可能性分为5类（参见ICH M7表1），并据此制订相应的控制措施。有时，一些显示出警示结构的杂质和合成工艺中产生的杂质可能无法获得诱变性数据（按ICHM7分类应为第3类），则应将这些杂质控制在等于或低于可接受限度内或诱变水平内（参考ICH M7注2），以厘清该杂质究竟是非诱变性（则应为第5类）还是诱变性（则应为第2类）。根据（Q）SAR方法学（电脑模拟研究）也可以预测细菌诱变检测的结果。根据ICH M7，应采用2个（Q）SAR方法学相互补充，其中一个应是依据专家规则，另一个则依据统计规则。应遵守OECD所设定的原则。

In orderto set an acceptable limit for (potential) mutagenic impurities in thesubstance it is necessary to divide the “acceptable intake” of the (potential)mutagenic impurity by the maximum daily dose of the substance. In order toidentify the acceptable intake for a mutagenic impurity, the“less-than-lifetime” (LTL) concept may be used. Note 7 of ICH M7 is veryhelpful to identify this acceptable intake, and ICH M7 also gives guidance onhow to identify acceptable total intakes for multiple impurities.

为了设定原料药中（潜在）诱变杂质的可接受限度，有必要根据原料药的最大日剂量对（潜在）诱变杂质的“可接受摄入量”进行区分。为了识别出诱变杂质的可接受摄入量，可以使用“小于生命周期”（LTL）概念。ICH M7注7在识别此可接受摄入量方面会很有用，ICH M7也给出如何识别多个杂质总体可接受摄入量的指南。

Once anacceptable limit is adequately identified, it is expected that a controlstrategy is developed according to the four proposals given by ICH M7 (fromoption 1 to option 4), according to the nature of those impurities and theirprobability to be present in the final substance. Batch data should be given insupport (if deemed necessary) and the analytical methods used should bedescribed. Purge studies may be developed in support to approaches based onoption 3 and option 4. Purge studies should be well-developed and justified andall the physico-chemical parameters used (reactivity, solubility, volatility,ionisability, physical processes, etc) should be given with the studies anddiscussed.

一旦对可接受限度进行充分的识别，则应根据这些杂质的属性，根据其在原料药成品中出现的可能性，以及根据ICHM7（方法1至方法4）所给出的4个方法建立控制策略。应提交批数据对其予以支持（如果认为有必要），应描述所用的分析方法。可以进行杂质清除研究以支持根据方法3和方法4所制订的方法。杂质清除研究应彻底并进行论证，在研究中所用的所有理化参数（反应性、溶解性、挥发性、离子化能力、物理处理等）均应同时提供并进行讨论。

Theimpurity profile of molecules identified as starting materials should be wellcharacterised. This means that applicants need to know what kind of impuritiescan be found in starting materials, in particular with regard to relatedsubstances since usually these are molecules that can react according to thechemistry foreseen by the process, leading to impurities in intermediates andpotentially in the final substance. Once the impurity profile of startingmaterials is sufficiently characterised a detailed discussion is expected notonly with regard to carryover of impurities from starting materials to thefinal substance but also with regard to their fate: what happens to them onceintroduced in the process along with the starting material. Carryover ofunreacted starting materials themselves should also be discussed. If deemednecessary, adequate evidence (e.g., analytical data, literature, informationfrom process development or process validation, etc.) should be given insupport.

定义为起始物料的分子的杂质概况应进行完整的确证。这意味着申报人需要知道在起始物料中可能会发现哪类杂质，尤其是有关物质，因为这些杂质是可以根据工艺进行预测的分子，会形成中间体中的杂质，并可能形成原料药成品中潜在的杂质。在充分确证了起始物料中的杂质概况后，不仅应对起始物料中杂质残留至原料药成品中的情况进行讨论，还应对其去向进行讨论：与起始物料一起引入工艺后它们发生了什么事情。未反应完全的起始物料自身在原料药成品中的残留也应进行讨论。如果认为有必要，应提交充分的证据（例如，分析数据、文献、工艺研发或工艺验证中所获得的数据等）予以支持。

Themanufacturing process should be described in details including all usedchemicals along with their quantities, all the operations conducted and all thecorresponding operational conditions adopted (in terms of temperatures,pressures, times, etc.). The process needs to be well-described since this isthe main source of information that allows assessors to take position onpotential formation of impurities and on the potential ability of the processto remove impurities. In-process controls should be mentioned in section S.2.2(as part of the description of the manufacturing process) and details should begiven in section S.2.4 (in terms of acceptance criteria and analyticalmethods), including controls implemented on isolated intermediates. It isexpected that no incongruences are noted while comparing information given inthese two sections of the dossier.

应详细描述生产工艺，包括所有使用的化学品及其用量、所有执行的操作以及所有采用的对应操作条件（温度、压力、时长等）。工艺应进行详细描述，因为这是评审人员获得信息的主要来源，依据这些信息，评审人员方可评估可能形成杂质的情况，以及工艺清除杂质的潜在能力。在S.2.2中应描述中控内容（作为生产工艺描述的一部分），在S.2.4中应提交详细信息（关于可接受标准和分析方法），包括对分离中间体所实施的控制。在注册文件中这两部分所提交的信息相比较不应有不一致的内容。

Themaximum batch size or the batch size range the process described in the dossierrefers to should be given in section S.2.2. This information should becongruent with the size of batches described in section S.4.4.

在S.2.2部分应提交注册文件中所述工艺的最大批量或批量范围。该信息应与S.4.4中所述的批量一致。

Theserequirements apply equally to the manufacturing steps for outsourced intermediates,which should be fully described in the CEP applications.

这些要求同等适用于外购中间体的生产步骤，这部分内容应在CEP申报资料中进行全面描述。